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Retinaldehyde Is a Substrate for Human Aldo-Keto Reductases of The Retinaldehyde is a substrate for human aldo-keto reductases of the 1C subfamily F Xavier Ruiz, Sergio Porté, Oriol Gallego, Armando Moro, Albert Ardèvol, Alberto del Río, Carme Rovira, Jaume Farrés, Xavier Parés To cite this version: F Xavier Ruiz, Sergio Porté, Oriol Gallego, Armando Moro, Albert Ardèvol, et al.. Retinaldehyde is a substrate for human aldo-keto reductases of the 1C subfamily. Biochemical Journal, Portland Press, 2011, 440 (3), pp.335-344. 10.1042/BJ20111286. hal-00658155 HAL Id: hal-00658155 https://hal.archives-ouvertes.fr/hal-00658155 Submitted on 10 Jan 2012 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Biochemical Journal Immediate Publication. Published on 18 Aug 2011 as manuscript BJ20111286 Specificity of human aldo-keto reductases 1C with retinaldehyde RETINALDEHYDE IS A SUBSTRATE FOR HUMAN ALDO-KETO REDUCTASES OF THE 1C SUBFAMILY F. Xavier Ruiz*, Sergio Porté*, Oriol Gallego*, Armando Moro*, Albert Ardèvol†,‡, Alberto Del Río*, Carme Rovira†,‡,§, Jaume Farrés* and Xavier Parés*1. From the Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Barcelona, Spain*; Laboratori de Modelització i Simulació Computacional, Parc Científic de Barcelona, Josep Samitier 1–5, E-08028 Barcelona†; Institut de Química Teòrica i Computacional (IQTCUB) ‡; and Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, E-08010 Barcelona§. 1 To whom correspondence should be addressed (email [email protected]) THIS IS NOT THE VERSION OF RECORD - see doi:10.1042/BJ20111286 Accepted Manuscript 1 Licenced copy. Copying is not permitted, except with prior permission and as allowed by law. © 2011 The Authors Journal compilation © 2011 Portland Press Limited Biochemical Journal Immediate Publication. Published on 18 Aug 2011 as manuscript BJ20111286 Specificity of human aldo-keto reductases 1C with retinaldehyde SYNOPSIS Human aldo-keto reductase 1C proteins (AKR1C1-AKR1C4) exhibit relevant activity with steroids, regulating hormone signaling at pre-receptor level. We here investigate the activity of the four human AKR1C enzymes with retinol and retinaldehyde. All the enzymes except AKR1C2 showed retinaldehyde reductase −1 activity with low Km values (~1 μM). The kcat values were also low (0.18 - 0.6 min ), except for AKR1C3 with 9-cis-retinaldehyde whose kcat was remarkably higher (13 min−1). Structural modeling of the AKR1C complexes with 9-cis-retinaldehyde indicated a distinct conformation of Trp-227, originated by changes in residue 226, which may contribute to activity differences. This was partially supported by the kinetics of the AKR1C3 R226P mutant. Retinol/retinaldehyde conversion, combined with the use of the inhibitor flufenamic acid, indicated a relevant role of endogenous AKR1Cs in retinaldehyde reduction in MCF-7 breast cancer cells. Overexpression of AKR1C proteins depleted retinoic acid (RA) trans-activation in HeLa cells treated with retinol. Thus, AKR1Cs may decrease RA levels in vivo. Finally, by using lithocholic acid as an AKR1C3 inhibitor and UVI2024 as an RA receptor antagonist, we provide evidence that the pro-proliferative action of AKR1C3 in HL-60 cells involves the RA signaling pathway and that this is in part due to the retinaldehyde reductase activity of AKR1C3. THIS IS NOT THE VERSION OF RECORD - see doi:10.1042/BJ20111286 Accepted Manuscript 2 Licenced copy. Copying is not permitted, except with prior permission and as allowed by law. © 2011 The Authors Journal compilation © 2011 Portland Press Limited Biochemical Journal Immediate Publication. Published on 18 Aug 2011 as manuscript BJ20111286 Specificity of human aldo-keto reductases 1C with retinaldehyde Short Title: Specificity of human aldo-keto reductases 1C with retinaldehyde Key words: aldo-keto reductase, retinaldehyde, retinoic acid, retinol, proliferation Abbreviation Footnote: ADH, alcohol dehydrogenase; AKR, aldo-keto reductase; AKR1B1, human aldose reductase; AKR1B10, human small intestine aldose reductase; AKR1C1-AKR1C4, human aldo-keto reductase 1C members; AKR1C7, bovine prostaglandin F synthase; MCF-7, breast adenocarcinoma epithelial cell line; MDR, medium-chain dehydrogenase/reductase; PPARγ, peroxisome proliferator-activated receptor gamma; RA, retinoic acid; RAR, retinoic acid receptor; RXR, retinoid X receptor; SDR, short- chain dehydrogenase/reductase; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis. THIS IS NOT THE VERSION OF RECORD - see doi:10.1042/BJ20111286 Accepted Manuscript 3 Licenced copy. Copying is not permitted, except with prior permission and as allowed by law. © 2011 The Authors Journal compilation © 2011 Portland Press Limited Biochemical Journal Immediate Publication. Published on 18 Aug 2011 as manuscript BJ20111286 Specificity of human aldo-keto reductases 1C with retinaldehyde INTRODUCTION Retinol (vitamin A) and its derivatives retinaldehyde and retinoic acid (RA) are essential for the formation and maintenance of many body tissues, such as skin, bone, and vasculature, as well as for the visual cycle (retinaldehyde) and immune function. They also play a role in reproduction, embryonic growth and development. RA is a morphogen and a key factor in the development of different vertebrate tissues and organs due to its ability to promote differentiation and apoptosis (for review [1]). RA has also a role in several pathological conditions, such as skin diseases, premature birth and rheumatoid arthritis. Various human cancers have altered retinoid metabolism and low RA levels, which favor tumor progression [2]. Conversion of retinol to RA requires several oxidative steps (Scheme 1). Members of three oxidoreductase superfamilies have been implicated in the reversible oxidation of retinol to retinaldehyde [3, 4]. The participation of cytosolic alcohol dehydrogenases (ADHs) from the medium-chain dehydrogenase/reductase (MDR) superfamily and of microsomal short-chain dehydrogenases/reductases (SDRs) has been deeply studied [4]. More recently, some members of the aldo-keto reductase (AKR) superfamily, such as chicken AKR1B12 [5], human aldose reductase (AKR1B1) and human small intestine aldose reductase (AKR1B10) [6], were defined as a novel group of cytosolic enzymes that could contribute to retinoid redox conversions. Comparison of the kinetic properties between members of the three superfamilies indicates similar Km values for retinol and retinaldehyde, while differences in kcat values determine the catalytic efficiency. Based on the cofactor specificity, ADHs (NAD-dependent) may work in the oxidative direction, AKRs (NADPH-dependent) in the reductive direction, while SDRs show examples of both specificities [3, 4]. AKR1C1-AKR1C4 (or human hydroxysteroid dehydrogenases, HSD) are cytosolic NADP-dependent monomeric dehydrogenases composed of 323 amino acid residues. They share 86% sequence identity and correspond to: AKR1C1 (20α(3α)- HSD); AKR1C2 (type 3 3α-HSD or bile-acid binding protein); AKR1C3 (type 2 3α- HSD or type 5 17β-HSD); and AKR1C4 (type 1 3α-HSD) [7]. The individual enzymes show different biochemical properties, such as substrate and inhibitor specificities, and expression patterns [8, 9]. The vast range of substrates used by human AKR1C members comprises steroids, prostaglandins, bile acids, trans-dihydrodiols of polycyclic aromatic hydrocarbons, and several endogenous and xenobiotic aldehydes and ketones. They are phase I drug-metabolizing enzymes for a variety of carbonyl-bearing compounds [7, 10, 11]. Transient transfection in COS-1 cells indicates that AKR1C enzymes function as ketosteroid reductases, transforming several steroid hormones or their precursors [7]. Thus, human AKR1C and members of other AKR subfamilies are involved in the pre- receptor regulation of nuclear (steroid hormone, peroxisome proliferator-activated, and orphan) receptors by controlling the local concentrations of their lipophilic ligands. THIS IS NOT THE VERSION OF RECORD - see doi:10.1042/BJ20111286 AKR1C3 is one of the most interesting enzymes, as it participates in androgen, estrogen and prostaglandin regulation, favoring pro-proliferative signals [12]. AKR1C genes are highly conserved in structure and may be transcriptionally regulated by different hormones and oxidative stress [13]. IncreasingAccepted evidence strongly supports Manuscript the involvement of AKR1Cs, and especially AKR1C3, in cancer development. They are found elevated in different cancer types [14-16]. They can participate in hormone-dependent malignancies by altering the steroid hormone levels [17, 18]. AKR1C overexpression promotes apoptosis resistance and cell survival, and prevents differentiation [14]. AKR1Cs are involved in cancer 4 Licenced copy. Copying is not permitted, except with prior permission and as allowed by law. © 2011 The Authors Journal compilation © 2011 Portland Press Limited Biochemical Journal Immediate Publication. Published on 18 Aug 2011 as manuscript BJ20111286 Specificity of human aldo-keto reductases 1C with retinaldehyde chemotherapeutic
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